Methods for use of branched amino acids

ABSTRACT

The invention provides an orally-administrable nutritional product comprising a dipeptide including a branched chain amino acids (BCAA). In one embodiment, the nutritional product comprises a dipeptide selected from at least one of the following: alanyl-leucine, alanyl-isoleucine, alanyl-valine, glycyl-leucine, glycyl-isoleucine, and glycyl-valine.

This application is a continuation of U.S. patent application Ser. No.12/089,970, filed Jun. 30, 2008, which is a U.S. national stage filingof International Appl. No. PCT/US2006/041615, filed Oct. 26, 2006, whichclaims priority to U.S. Provisional Appl. No. 60/731,450, filed Oct. 28,2005, the entire contents of which are expressly incorporated herein byreference thereto.

BACKGROUND OF THE INVENTION

1. Technical Field

The invention relates generally to use of branched chain amino acids andmore particularly to the use of dipeptides including branched chainamino acids to reduce bitterness in orally-administrable nutritionalproducts.

2. Background Art

Amino acids are the monomeric building blocks of proteins, which in turncomprise a wide range of biological compounds, including enzymes,antibodies, hormones, transport molecules for ions and small molecules,collagen, and muscle tissues. Amino acids are considered hydrophobic orhydrophilic, based upon their solubility in water, and, moreparticularly, on the polarities of their side chains. Amino acids havingpolar side chains are hydrophilic, while amino acids having nonpolarside chains are hydrophobic. The solubilities of amino acids, in,part,determines the structures of proteins. Hydrophilic amino acids tend tomake up the surfaces of proteins while hydrophobic amino acids tend tomake up the water-insoluble interior portions of proteins.

Of the common 20 amino acids, nine are considered essential in humans,as the body cannot synthesize them. Rather, these nine amino acids mustbe obtained through an individual's diet. A deficiency of one or moreamino acids can cause a negative nitrogen balance, wherein more nitrogenis excreted than is ingested as proteins are degraded faster than theyare synthesized. Such a condition can lead to disruption of enzymaticactivity and the loss of muscle mass.

A number of muscle-wasting conditions have been identified, for whichtreatment with amino acid supplements has proved beneficial. Forexample, cachexia is a severe body wasting condition characterized bymarked weight loss, anorexia, asthenia, and anaemia. Cachexia is acommon feature of a number of illnesses, such as cancer, sepsis, chronicheart failure, rheumatoid arthritis, and acquired immune deficiencysyndrome (AIDS). In addition, it has been found that certain tumors mayinduce cachexia through the production of a 24 kDa glycoprotein calledproteolysis-inducing factor (PIF). PIF decreases protein synthesis,activates protein degradation, and stimulates theATP-proteasome-dependent pathway. It has been hypothesized that thedecreased protein synthesis associated with PIF is the result of PIF'sability to block the translation process of protein synthesis. Anotherfactor, Angiotensin II (Ang II) has shown similar effects and may beinvolved in the muscle wasting observed in some cases of cachexia. Othermuscle wasting diseases and disorders are known, including, for example,sarcopenia, an age-related loss of muscle mass.

Treatment of conditions such as cachexia and sarcopenia often includesnutritional supplementation, and, in particular, amino acidsupplementation, in an attempt to increase protein synthesis and/orcounteract protein degradation. Branched chain amino acids (BCAAs),which include valine, leucine, and isoleucine, are especially useful insuch cases, as they have been shown to function not only as proteinbuilding blocks, but also as inducers of signal transduction pathwaysthat modulate translation initiation.

The wasting conditions above are just a few of the conditions,disorders, and diseases for which amino acid supplementation has provedbeneficial. Amino acid supplementation has also been used to treatdiabetes, hypertension, high levels of serum cholesterol andtriglycerides, Parkinson's disease, insomnia, drug and alcoholaddiction, pain, insomnia, and hypoglycemia. Supplementation with BCAAs,in particular, has been used to treat liver disorders, includingcompromised liver function, including cirrhosis, gall bladder disorders,chorea and dyskinesia, and kidney disorders, including uremia. BCAAsupplementation has also proved successful in the treatment of patientsundergoing hemodialysis, resulting in improvements in overall health andmood.

Unfortunately, BCAAs exhibit a strongly bitter taste. Some patientsreject oral nutritional supplements containing BCAAs because of theirobjectionable taste, despite the physiological benefits such supplementsoffer. Attempts to overcome such rejection have included the addition ofmasking agents to the supplement, which attempt to block the perceptionof bitterness, and the addition of other strong flavors, such aschocolate mint. Neither of these attempts has proved satisfactory.Masking agents generally do not completely block a patient's perceptionof bitterness and the addition of other strong flavors, while notbitter, are often equally objectionable to patients with limitedappetites and/or nausea.

Accordingly, there is a need in the art for an orally-administrablenutritional product and method for its administration that do not sufferfrom the deficiencies above.

SUMMARY OF THE INVENTION

The invention provides an orally-administrable nutritional productcomprising a dipeptide including a branched chain amino acid (BCAA). Thenutritional products of the present invention may be used to maintain orpromote a nitrogen balance in an individual suffering from a disease,disorder, stress, or a consequence of aging. The products of the presentinvention may similarly be used to maintain or promote a nitrogenbalance in an otherwise healthy individual but who may be at risk fordeveloping a nitrogen imbalance, such as an individual engaged inathletic performance or other physically strenuous activity. In oneembodiment, the nutritional product comprises a dipeptide selected fromat least one of the following: alanyl-leucine, alanyl-isoleucine,alanyl-valine, glycyl-leucine, glycyl-isoleucine, and glycyl-valine.

A first aspect of the invention provides an orally-administrablenutritional product comprising: at least one dipeptide including atleast one branched chain amino acid, wherein the at least one dipeptideexhibits a bitterness less than that of a free branched chain aminoacid.

A second aspect of the invention provides a method of treating anindividual suffering from at least one of a disease and a disorder withan orally-administrable nutritional product, the method comprising:administering to the individual an orally-administrable nutritionalproduct including: an effective amount of at least one dipeptideincluding at least one branched chain amino acid, wherein the dipeptideexhibits a bitterness less than that of a free branched chain aminoacid.

The illustrative aspects of the present invention are designed to solvethe problems herein described and other problems not discussed, whichare discoverable by a skilled artisan.

DETAILED DESCRIPTION

As indicated above, the present invention relates to the use of adipeptide including a branched chain amino acid (BCAA) to reducebitterness in an orally-administrable nutritional product.

As used herein, the terms “treatment” and “treat” refer to bothprophylactic or preventive treatment and curative or disease-modifyingtreatment, including treatment of patients at risk of contracting adisease or suspected to have contracted a disease, as well as patientswho are ill or have been diagnosed as suffering from a disease ormedical condition. The terms “treatment” and “treat” also refer to themaintenance and/or promotion of health in an individual not sufferingfrom a disease but who may be susceptible to the development of anunhealthy condition, such as nitrogen imbalance, due to, for example,strenuous physical activity, Consequently, an “effective amount” is anamount that treats a disease or medical condition in an individual or,more generally, provides a nutritional, physiological, or medicalbenefit to the individual.

Surprisingly, it has been found that dipeptides of a branched chainamino acid (BCAA) and a second amino acid do not exhibit the bitternessof the free branched chain amino acid. A dipeptide is formed by thejoining of the α-carboxyl group of one amino acid to the α-amino groupof another amino acid. In one preferred dipeptide of the presentinvention, the second amino acid is alanine. In another preferreddipeptide of the present invention, the second amino acid is glycine.The preferred dipeptides according to the present invention, therefore,arealanyl-leucine, alanyl-isoleucine, alanyl-valine, glycyl-leucine,glycyl-isoleucine, and glycyl-valine. It should be recognized, however,that any amino acid may be used in the dipeptides of the presentinvention, including a second BCAA. The dipeptides of the presentinvention may be produced by any known or later-developed method,including synthetic production.

Equal molar concentrations of free leucine and the alanyl-leucinedipeptide were tasted after being dissolved in water and after beingadded to a standard vanilla oral nutritional supplement. In eachinstance, the alanyl-leucine dipeptide was found to exhibit lessbitterness than free leucine. The tests were repeated, comparing freeisoleucine to the alanyl-isoleucine dipeptide and free valine to thealanyl-valine dipeptide. Again, in each instance, the dipeptide wasfound to exhibit less bitterness than the free BCAA. The dissolvedalanyl-leucine dipeptide was also compared to Novartis' RESOURCE®Support®, a nutritional product containing approximately 3.2 g of freeleucine per 8 oz. serving. The dissolved alanyl-leucine dipeptideexhibited less bitterness than RESOURCE® Support®.

Accordingly, the present invention includes orally-administrablenutritional products that substitute, in whole or in part, a dipeptideincluding a BCAA for the free BCAA normally used. As noted above,preferred dipeptides include one of alanine and glycine and a BCAA,specifically alanyl-leucine, alanyl-isoleucine, alanyl-valine,glycyl-leucine, glycyl-isoleucine, and glycyl-valine dipeptides. Theorally-administrable nutritional product of the present invention mayfurther contain any number of ingredients that provide a nutritional,physiological, or medical benefit to an individual. Such ingredientsinclude, for example, proteins, soluble and/or insoluble fibers, fattyacids, vitamins, minerals, sugars and/or other carbohydrates, flavoragents, and medicaments or other therapeutic agents. The presentinvention further includes methods for the administration of suchorally-administrable nutritional products to an individual.

The products and methods of the present invention may be used,therefore, to treat an individual suffering from one or more of thefollowing: cachexia, cancer, tumor-induced weight loss, sepsis, chronicheart failure, rheumatoid arthritis, acquired immune deficiency syndrome(AIDS), sarcopenia, diabetes, hypertension, high levels of serumcholesterol, high levels of triglycerides, Parkinson's disease,insomnia, drug addiction, alcohol addiction, pain, insomnia,hypoglycemia, compromised liver function, including cirrhosis, gallbladder disorders, chorea, dyskinesia, and a kidney disorder, includinguremia. In addition, the products and method of the present inventionmay be used to treat an individual undergoing hemodialysis.

The foregoing description of various aspects of the invention has beenpresented for purposes of illustration and description. It is notintended to be exhaustive or to limit the invention to the precise formdisclosed, and obviously, many modifications and variations arepossible. Such modifications and variations that may be apparent to aperson skilled in the art are intended to be included within the scopeof the invention as defined by the accompanying claims.

What is claimed is:
 1. A method of treating an individual suffering fromat least one of cachexia, cancer, tumor-induced weight loss, sepsis,chronic heart failure, rheumatoid arthritis, acquired immune deficiencysyndrome (AIDS), sarcopenia, diabetes, hypertension, high levels ofserum cholesterol, high levels of triglycerides, Parkinson's disease,insomnia, drug addiction, alcohol addiction, pain, hypoglycemia, gallbladder disorders, chorea, dyskinesia, or a kidney disorder , the methodcomprising: administering to the individual an orally-administrablenutritional product including: an effective amount of at least onedipeptide including at least one branched chain amino acid, wherein theat least one dipeptide exhibits a bitterness less than that of a freebranched chain amino acid, and wherein the at least one dipeptidecomprises alanyl-isoleucine.
 2. The method of claim 1, wherein theorally-administrable nutritional product further comprises at least oneof a fiber, a fatty acid, a vitamin, a mineral, a sugar, a carbohydrate,a flavor agent, a medicament, and a therapeutic agent.
 3. The method ofclaim 1, wherein the orally-administrable nutritional product furthercomprises at least one of each of a protein, a fatty acid, and acarbohydrate.
 4. The method of claim 3, wherein the orally-administrablenutritional product further comprises at least one fiber.
 5. The methodof claim 4, wherein the orally-administrable nutritional product furthercomprises at least one vitamin, and at least one mineral.
 6. The methodof claim 4, wherein the orally-administrable nutritional product furthercomprises at least one flavor agent.
 7. The method of claim 1, whereinthe orally-administrable nutritional product further comprises amedicament or a therapeutic agent, and at least one of each of aprotein, a fatty acid, and a carbohydrate.
 8. The method of claim 1,wherein the orally-administrable nutritional product further comprisesat least one of each of a protein, a fiber, a fatty acid, a vitamin, amineral, a carbohydrate, a flavor agent, and a medicament.
 9. A methodof treating an individual suffering from uremia with anorally-administrable nutritional product, the method comprising:administering to the individual suffering from uremia anorally-administrable nutritional product including: an effective amountof at least one dipeptide including at least one branched chain aminoacid, wherein the dipeptide exhibits a bitterness less than that of afree branched chain amino acid, and wherein the dipeptide is selectedfrom the group consisting of alanyl-leucine, alanyl-isoleucine,alanyl-valine, and combinations thereof.